Liver transplantation for intrahepatic cholangiocarcinoma: a propensity score-matched analysis

Liver resection (LR) is the only recommended effective curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis of patients with ICC is still poor even after curative resection. Recently, many researchers focused on the therapeutic value of LT for patients with ICC. This study aimed to identify the role of liver transplantation in patients with ICC by internally comparing with LR in ICC and externally comparing with LT in HCC. We obtained patient data from SEER database. Propensity score methods were applied to control confounders. Survival outcome was estimated using Kaplan–Meier survival curves and compared using the log-rank test. A total of 2538 patients with ICC after surgery and 5048 patients with HCC after LT between 2000 and 2019 were included in this study. The prognosis of patients with ICC after LT were better than patients with ICC after LR in both unmatched (HR 0.65, P = 0.002) and matched cohorts (HR 0.62, P = 0.009). The 5-year OS rate after LT could be improved to 61.7% in patients with local advanced ICC after neoadjuvant chemotherapy. In conclusion, our study demonstrated that the prognosis of patients with ICC after LT was better than patients with ICC after LR, but was still worse than patients with HCC after LT. LT with neoadjuvant chemotherapy should be considered as a treatment option for patients with locally advanced ICC, but more prospective multicenter clinical trials are needed to further confirm these results.


Results
Patient and Tumor characteristics. A total of 2538 patients with ICC who underwent curative surgery and 5048 patients with HCC who underwent LT were enrolled in this study. Among the 2538 patients with ICC, most (95.5%) underwent LR, and only 113 (4.5%) underwent LT. Patients with ICC in the LT cohort were younger (57 vs. 65; p < 0.001) and had a male predilection (66.4% vs. 48.9%; p < 0.001) as compared to those in the LR cohort. The tumor characteristics also differed between the patients in LR and LT cohorts. Patients with an early AJCC stage, small tumor size, well-differentiated tumor grade and cirrhosis were more likely to undergo LT (p < 0.01). After PSM, no significant differences were observed between the patients in LR and LT cohorts. The baseline characteristics of the unmatched and matched cohorts are shown in Table 1.  Table 2). The 5-year OS rates in patients undergoing LT and LR were 52.8% and 29.9% in the matched cohorts, respectively.

Overall survival comparation between LR and LT in the ICC patients.
Overall survival analysis by different selection criteria in the ICC patients receiving LT. As previously mentioned, two potential selection criteria were identified for patients with ICC undergoing LT. Herein, we defined criteria 1 as: very early stage tumor (tumor size ≤ 2 cm) + cirrhosis; and criteria 2 as: locally advanced tumor (AJCC stage I and II) + chemotherapy. After selection, 10 patients with ICC undergoing LT met the criteria 1 and 31 patients with ICC undergoing LT met the criteria 2. Survival analyses were performed for the different patient subgroups. The 5-year OS rate for patients undergoing LT who met selection criteria 1 and 2 were 43.8% and 61.7%, respectively ( Table 3). The survival outcome in patients within selection criteria 1 or 2 was significantly better than patients beyond both selection criteria (p = 0.01) ( Fig. 2A). Furthermore, we also applied Milan criteria (single tumor ≤ 5 cm or 3 tumors all ≤ 3 cm with no angioinvasion or extrahepatic involvement) to select ICC patients who underwent LT. After selection, 47 patients with ICC within Milan criteria underwent LT and 5-year OS rate of them was 56.4%. 66 patients with ICC beyond Milan criteria underwent LT and 5-year OS rate of them was 50.1% (Table 4). No significant difference in survival outcome was observed between patients within or beyond Milan criteria (p = 0.68) (Fig. 2B).  Table 5).

Discussion
Currently, LR is the only widely accepted curative treatment for ICC. However, the 5-year OS rate in patients with ICC after LR has been reported to be 20-40% [17][18][19] . This was verified in our study, in which the 5-year OS rates in patients with ICC after LR were 33.3% and 29.9% in unmatched and matched cohorts, respectively. The 5-year OS rate in patients with ICC after LT was 52.8%, which was significantly higher than that in patients with ICC following LR (HR = 0.62, p = 0.009). The results of our study are encouraging because it is generally accepted www.nature.com/scientificreports/ in the transplant community that a 5-year OS rate of at least 50-60% is required for a transplant indication to be considered acceptable 20 .
In the recent years, the two potential selection criteria defined for patients with ICC undergoing LT are as follows: ①very early stage tumor (single tumor, tumor size ≤ 2 cm) with cirrhosis; and ②locally advanced tumor with neoadjuvant chemotherapy 11,15 . Our study analyzed the survival outcomes of the selected patients with ICC after LT based on these two criteria. We found that the 5-year OS rate after LT improved to 61.7% in patients with locally advanced ICC after neoadjuvant chemotherapy. However, a 5-year OS rate of 43.8% was observed in patients with very early stage ICC with cirrhosis. This unsatisfactory result could be owing to the relatively small sample size (only 10 patients with ICC had tumor size ≤ 2 cm and cirrhosis). www.nature.com/scientificreports/ Regardless of the underlying disease, the goal of LT is to provide liver recipients with the maximum possible benefit from the limited donor liver source 10,21 . Thus, only the survival superiority of LT over LR or a 5-year OS rate of 61.7% did not justify LT indication in patients with ICC. Our study further analyzed the survival outcomes in patients with ICC undergoing LT compared to those in patients with HCC. However, the prognosis of ICC in patients after LT was worse than that of HCC in patients (HR: 2.14, p < 0.001).
Notably, the OS in the selected patients with ICC who underwent LT has significantly improved in some centers. Sapisochin et al. reported that patients with cirrhosis and very early-stage ICC (single tumor ≤ 2 cm) had good survival outcomes after LT (1-year OS: 93%, 3-year OS rate: 84% and 5-year OS rate: 65%) 22 . Lunsford et al. further reported that patients with locally advanced ICC who showed pre-transplant disease stability after neoadjuvant therapy benefited from LT. The 1-year, 3-year and 5-year OS rates were 100%, 83.3% and 83.3% respectively, although it should be noted that the sample size of this study was very small (6 patients with ICC after LT) 23 . These findings indicate the promising prospects of LT in selected patients with ICC.

Conclusion
In conclusion, our study analyzed the survival outcomes in patients with ICC undergoing LT compared to those in patients with ICC after LR and in patients with HCC after LT. Our results demonstrated that patients with ICC after LT had a better prognosis than those after LR and the 5-year OS rate after LT was improved to 61.7% in patients with local advanced ICC after neoadjuvant chemotherapy. However, the prognosis of ICC in patients after LT was worse than that of HCC in patients after LT, which questioned the justification of performing LT in patients with ICC. LT with neoadjuvant chemotherapy should be considered as a treatment option for patients with locally advanced ICC; however, more prospective multicenter clinical trials are needed to confirm these results.